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Once translocated into the cytosol of target cells, the catalytic domain (AC) of the adenylate cyclase toxin (CyaA), a major virulence factor of Bordetella pertussis, is potently activated by binding calmodulin (CaM) to produce supraphysiological levels of cAMP, inducing cell death. Using a combination of small-angle X-ray scattering (SAXS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), and synchrotron radiation circular dichroism (SR-CD), we show that, in the absence of CaM, AC exhibits significant structural disorder, and a 75-residue-long stretch within AC undergoes a disorder-to-order transition upon CaM binding. Beyond this local folding, CaM binding induces long-range allosteric effects that stabilize the distant catalytic site, whilst preserving catalytic loop flexibility. We propose that the high enzymatic activity of AC is due to a tight balance between the CaM-induced decrease of structural flexibility around the catalytic site and the preservation of catalytic loop flexibility, allowing for fast substrate binding and product release. The CaM-induced dampening of AC conformational disorder is likely relevant to other CaM-activated enzymes.

Original publication




Journal article


PLoS biology

Publication Date





Institut Pasteur, UMR CNRS 3528, Chemistry and Structural Biology Department, Paris, France.


Bordetella pertussis, Adenylate Cyclase Toxin, Calmodulin, Cyclic AMP, Deuterium Exchange Measurement, Circular Dichroism, Calcium Signaling, Catalytic Domain, Protein Conformation, Protein Binding, Catalysis, Synchrotrons, Models, Molecular, Mass Spectrometry, Scattering, Small Angle